Histone deacetylase inhibitors (HDACi) are an important class of emerging therapeutics, approved for three rare cancers. HDACi's elicit complex cellular responses by blocking HDAC enzymes to promote acetylation of both histones and non-histone proteins. In genetic disorders, HDACi-induced histone modification can result in increased or decreased transcriptional expression of mutated gene(s) of interest but also confer indirect benefits through non-histone proteins (such as transcription factors and heat shock proteins) that modulate chaperone and proteostatic networks. Because of their broad effects on transcription, maximizing HDACi efficacy while limiting the dose is a major challenge in HDACi therapy. In developing and validating a therapeutic strategy that lowers HDACi dosage but also treats both systemic and cerebral disease, the latter presents additional challenges because it requires effective HDACi penetration across the blood brain barrier while also allowing brain HDAC function and in particular, Purkinje cell restoration, which requires HDAC3.
Niemann-Pick Type C disease (NPC) is an autosomal recessive neurodegenerative disease caused by defect in either Npc1 or Npc2 genes. 95% of NPC cases are due to defect in Npc1. The physiological function of both Npc1 and Npc2 are in the transport of cellular cholesterol. Cells with defects in these genes accumulate cholesterol primarily in late endosomal lysosomal system because of a block in cholesterol transport from the lysosome to the ER. Insertion of a point mutation in Npc1 gene that blocks cholesterol transport in cells confers neurodegenerative disease in a mouse model, providing definitive molecular evidence that NPC1 protein function is critical for disease. In NPC patients, progressive neurodegeneration is a hallmark of the NPC disease. Disease progression can be heterogeneous, and neurodegenerative decline may span one to two decades, but once initiated, leads to fatal outcomes. In early onset, splenomegaly and hepatomegaly are common presenting symptoms followed by neurocognitive and neuromuscular degeneration.
At present, the only available treatment for NPC is miglustat, an iminosugar marketed under the trade name, Zavesca™. It was developed to treat type 1 Gaucher's disease, another lysosomal disorder that arises from accumulation of glycosphingolipids. Miglustat acts as a substrate reduction therapy to decrease sphingolipids. Zavesca™ is approved for NPC treatment in Europe, Canada and Japan but was denied FDA approval because of insufficient data. Zavesca™ is therefore prescribed off-label in the U.S. It confers mild improvement in clinical neurological symptoms but fails to prevent disease progression.
2-Hydroxypropyl-β-cyclodextrin (HPBCD) is under trial as an emerging therapy. HPBCD chelates cholesterol and has therefore been proposed as a potential therapy for NPC, but it does not cross the blood brain barrier (BBB).
Generally, systemic drug delivery primarily benefits the liver and other organ systems of the body cavity, while direct drug delivery into the central nervous system (CNS) is needed for substantial neurological improvement. Direct CNS delivery inheres several disadvantages, however. It increases the procedural risk in lifelong therapies, is associated with hearing loss, and provides little or no benefit for systemic disease. The present inventors have found that there is a need for a simplified therapeutic approach to integrate the treatment of both cerebral and systemic defects in challenging genetic diseases such as NPC.